Parenteral aqueous tetracycline composition containing n, n-dimethylacetamide solvent



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United States Patent ()fifi cc 3,070,502 Patented Dec. 25, 1962 PARENTERAL AQUEOUS TETRACYCLINE COM- POSITION CONTAINING N,N-DIMETHYLACET- AMIDE SOLVENT Harry Spounoble, Kalamazoo Township, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed June 17, 1958, Ser. No. 742,480

- 2 Claims. (Cl. 167-65) This invention relates to a pharmaceutical composition and more particularly to an, injectable pharmaceutical composition comprising tetracycline and special solvent therefor. I

Tetracyclineisa well-known broad spectrum antibiotic. It is available as the free base and as a salt, for 1 example, tetracycline hydrochloride.

Notwithstanding the normal acceptability of oral dosage forms of tetracycline, a need exists for an elegant injectable composition, especially for individuals who are unable to take or tolerate this valuable'antibiotic'in oral dosage forms and in those circumstances where quick, high blood levels are desirable.

It is an object therefore, of the instant invention to provide injectable pharmaceutical preparations contain- 25 ing tetracycline. An additional objectis to provide such injectable preparations which give high blood levels of the active ingredient. A further object is to provide such preparations which are stable and pharmaceutically acceptable. Other objects will be apparent to those skilled in the art to which this invention pertains.

The foregoing and additional objects have been accorn I plished by the provision of an injectable pharmaceutical composition comprising N,N-dimethylacetamide and tetracycline.

As used in the specification and claims, tetracycline is intended to include the free acid and the therapeutically active salts thereof. Illustrative salts of tetracycline include the following: the hydrochloride and the phosphate complex.

Broadly described, this invention contemplates the use of N,N-dimethylacetamide as a solvent for preparing injectable solutions of tetracycline. The said solutions can be made available to the practitioners in a form ready for immediate injection or in a form for extemporaneous preparation of the injectable solution.

The amount of the principal active ingredient of the novel composition, i.e, tetracycline, can vary over a.

considerable range. From about 0.5 percent weight/ volume .to about fifty percent weight/volume can be utilized; however, from about 2.5 percent weight/volume to about 25 percent weight/volume is preferred depending on the age and condition of the patient.

The concentration of N,N-dimethylacetamide used can vary between about five percent volume/volume and ninety percent volume/volume.

Various complementary active ingredients can be added to the novel compositions of the invention. Illus tratively, but not limiting, the following can be utilized: other antibiotics such as penicillins, streptomycin, erythromycin, oxytetracycline, chlortetracycline and novobiocin; corticosteroids such as hydrocortisone, prednisolone, prednisone, 6-methylprednisolone, 9-alpha-fiuoro- 16-alphahydroxyprednisolone; vitamins such as the folic acid, nicotinamide, B complex vitamins, ascorbic acid; and the like.

Useful supplementary ingredients in the novel compositions are preservatives, for example, benzyl alcohol, chlo- 5 robutanol, methylparaben, propylp'araben, and quaternary ammonium compounds; isotonic agents, for exam-' ple, lactose, sodium chloride, dextrose and sucrose; stabilizers, for example, nicotinamide; and butters. The compositions of the invention possess utility in 10 the treatment of a wide range of infectious diseases, for example, Rocky Mountain spotted fever, typhus, Q fever, Bril l s disease, primary atypical pneumonia and many more.

In addition to producing an elegant pharmaceutical preparation, the use of N,N-dimethylacetamide, espe v cially in combination with benzyl alcohol, also produces higher. serum levels v of tetracycline after parenteral administration. This is shown by the data given in the tables following Example 4.

The following examples set forth the best mode con templated of carrying out the invention but are not to be construed as limiting.

EXAMFLE 1.j-INJECTABLE SOLUTION A. 1000 milliliterslof an injectable solution are prewpared from the following types and amounts of ingredi cuts.

' Each milliliter:

. Total 55 mg. tetracycline hydrochloride grams 55 i 25 mg. lactose do 25 9 mg. benzyl alcohol;' ;Z; ;..;do ""9 10 percent v./v. N,N-dimethylacetamide millilitersL... 1 00 Q.s. water for injection ad 1000 milliliters.

The N,N-dimethylacetamide is dissolved in part of the water for injection. The solid ingredients are dissolved in this solution. The solutionis brought up just short ofthe final volume and the benzyl alcohol is added and' mixed well until dissolved. The solution is then made up to final volume with water for injection, sterilizedby passage through a sterilized bacterial filter and filled into five-milliliter ampoules under aspetic conditions.

equivalent amount of tetracycline phosphate complex, 67 grams of the complexwould be substituted forthe hydrochloride in the above formula.

EXAMPLE 2".-INJECTABLE SOLUTION Five liters of an injectable solution are prapared from the following types andamounts of ingredients.

Each milliliter: "Total P 100 mg. tetracycline acid .grams 500 9 mg. benzyl alcohol do 45 75 percent v./v. N,N-dimethylacetamide milliliters 3750 Q.s. water for injection ad 5000 milliliters.

conditions into one-milliliter ampoules.

B. To produce a similar preparation containing an" These data clearly show that higher blood levels are obtained by the use of the DMA containing vehicles than those without DMA. Moreover, the blood leve.s ob- 60 tained by the use of the combination of DMA with benzyl alcohol are unexpectedly higher than those obtained by either DMA or benzyl alcohol without the other.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described herein, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

What is claimed is:

70 1. An injectable therapeutic composition comprising from about 0.5 percent to about fifty percent weight/ volume of tetracycline as the essential active ingredient in an aqueous solvent vehicle comprising from about five percent to about ninety percent volume/volume of 75 NQN-dimethylacetamide.

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,N-dimethylacet- 65 This solution is then made up to volume with water for injection. The whole is then sterilized by pasred he lower pper Qiluent; One thousand ampoules of diluent are pared from the following types and amounts of rials:

10 percent vJv. N,N-dimethylacetamide 9 mg. benzyl "alcohol Q.s water for injection ad 4700 milliliters.

Thebenzyl alcohol is dissolved in the N amide.

sage through a bacterial filter, and 4.7 cc. of sterile s0lution is filled into each ampoule under aseptic conditions. The ampoules are heat sealed. The diluent is added under aseptic conditions, at the same when it is desi to 'prepare the injectable composition. A unit package, wherein the dry active ingredient is placed in t compartment of a vial and the sterile diluent in the u compartment can be "used advantageously.

5 6 261110 composition of claim 1 wherein a minor pro- OTHER REFERENCES Of .benzyl 81601101 is included as a Part of the Vandernbelt et 211.: Science, vol. 121, April 29, 1955, solvent vehlcle. pages 1 References Cited in the file of this patent g g g Bunetm AuuSt UNITED STATES PATENTS Ashton: Chemistry and Industry, September 17, 1955, 2,671,748 Crooks Mar. 9, 1954 P 1183- 2 9 0 5 4 Hammer APL181961 GHIIS: I.A.'P.A., SCI. ECL, V01- 45, N0- 10, OCtObeI' 2,990,331 Neumann et a1 June 27, 1961 1957 587-591 (65P- 5 Kostenbauder: I.A.P.A., SCI. Ed., v01. (1956), pp. FOREIGN PATENTS 518 et 91,111 Norway Jan, 4, 1958 Dispensatory of the U.S.A., 25th Ed., 1955, LR. Lippincott, page 159. 

1. AN INJECTABLE THERAPEUTIC COMPOSITION COMPRISING FROM ABOUT 0.5 PERCENT TO ABOUT FIFTY PERCENT WEIGHT VOLUME OF TETRACYCLINE AS THE ESSENTIAL ACTIVE INGREDIENT IN AN AQUEOUS SOLVENT VEHICLE COMPRISING FROM ABOUT FIVE PERCENT TO ABOUT NINETY PERCENT VOLUME/VOLUME OF N,N-DIMETHYLACETAMIDE. 